Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation.
Peripheral inflammation leads to a number of centrally mediated physiological and behavioral changes. The underlying mechanisms and the signaling pathways involved in these phenomena are not yet well understood. We hypothesized that peripheral inflammation leads to increased neuronal excitability arising from a CNS immune response. We induced inflammation in the gut by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to adult male rats. To examine the excitability of the brain in vivo, we administered pentylenetetrazole (PTZ; a GABAergic antagonist) intravenously to evoke clonic seizures. Rats treated with TNBS showed increased susceptibility to PTZ seizures that was strongly correlated with the severity and progression of intestinal inflammation. In vitro hippocampal slices from inflamed, TNBS-treated rats showed increased spontaneous interictal burst firing following application of 4-aminopyridine, indicating increased intrinsic excitability. The TNBS-treated rats exhibited a marked, reversible inflammatory response within the hippocampus, characterized by microglial activation and increases in tumor necrosis factor alpha (TNFalpha) levels. Central antagonism of TNFalpha using a monoclonal antibody or inhibition of microglial activation by i.c.v. injection of minocycline prevented the increase in seizure susceptibility. Moreover, i.c.v. infusion of TNFalpha in untreated rats for 4 days also increased seizure susceptibility and thus mimicked the changes in seizure threshold observed with intestinal inflammation. Our finding of a microglia-dependent TNFalpha-mediated increase in CNS excitability provides insight into potential mechanisms underlying the disparate neurological and behavioral changes associated with chronic inflammation.
Riazi
Kiarash
K
Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity, and Inflammation, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Galic
Michael A
MA
Kuzmiski
J Brent
JB
Ho
Winnie
W
Sharkey
Keith A
KA
Pittman
Quentin J
QJ
D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000276:immunology / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid